Formation of n-protected 3,6-bis-(4-aminobutyl)-2,5-diketopiperazine through a cyclic alpha-n-protected amino ester intermediate

Abstract

A method for the synthesis of N-protected 3,6-aminoalkyl-2,5-diketopiperazines is provided. The method includes obtaining a cyclic α-N protected active amino ester and adding it to a mixture of an amine catalyst in an organic solvent.

1 - 20 . (canceled) 
     
     
         21 . A method for the synthesis of a compound according to Formula I: 
       
         
           
           
               
               
           
         
         the method comprising mixing a cyclic amino compound according to the following formula: 
       
       
         
           
           
               
               
           
         
         with a first organic solvent to form a first mixture,
 adding the first mixture over a predetermined period of time to a mixture of catalyst in an organic solvent selected from THE, dioxane, and ethanol to form a reaction mixture, 
 combining the reaction mixture with a second solvent to quench the reaction, 
 wherein the cyclic amino compound is added over a period of greater than one hour, 
 wherein R is a C3 to C5 N-protected alkyl amine, 
 wherein the protecting group (PG) is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups, 
 wherein n is from 2-4, and 
 wherein X is selected from C, P, and S. 
 
       
     
     
         22 . The method of  claim 21 , wherein the reaction mixture is heated to a temperature of up to 75° C. 
     
     
         23 . The method of  claim 21 , wherein the reaction mixture is heated for a period of 2 to 6 hours. 
     
     
         24 . The method of  claim 21 , wherein the organic solvent is THF. 
     
     
         25 . The method of  claim 21 , wherein the second solvent is water. 
     
     
         26 . The method of  claim 25 , wherein the amine catalyst is benzamindoxine. 
     
     
         27 . The method of  claim 26 , wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide. 
     
     
         28 . The method of  claim 27 , wherein the co-catalyst is present in an amount of about 0.2 equivalents that of the catalyst. 
     
     
         29 . The method of  claim 21 , wherein the wherein the catalyst is present in an amount of 0.25 to 2.5 equivalents based on the amount of the cyclic amino compound. 
     
     
         30 . The method of  claim 29 , wherein the organic solvent is selected from THF and ethanol. 
     
     
         31 . The method of  claim 21 , wherein the PG is selected from trifluoroacetyl, Cbz, and Boc. 
     
     
         32 . The method of  claim 21 , wherein X is C. 
     
     
         33 . The method of  claim 32 , wherein PG is trifluoroacetyl. 
     
     
         34 . The method of  claim 33 , wherein the first organic solvent is selected from THF and ethanol. 
     
     
         35 . A method for the synthesis of a diketopiperazine according to Formula II, 
       
         
           
           
               
               
           
         
         the method comprising mixing a cyclic amino compound according to the following formula: 
       
       
         
           
           
               
               
           
         
         with a first organic solvent to form a first mixture,
 mixing the first mixture with an amine catalyst in an organic solvent selected from THE, dioxane, and ethanol to form a reaction mixture, 
 heating the reaction mixture for a period of 2 to 6 hours, and removing the PG after formation of diketopiperazine, 
 wherein R is a C4 N-protected alkyl amine, 
 wherein the protecting group (PG) is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups, and 
 wherein X is selected from C, P, and S. 
 
       
     
     
         36 . The method of  claim 35 , wherein the mixture is heated to a temperature of 40° C. to 75° C. 
     
     
         37 . The method of  claim 36 , wherein the first organic solvent is THF. 
     
     
         38 . The method of  claim 35 , wherein the amine catalyst is benzamindoxine. 
     
     
         39 . The method of  claim 38 , wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide. 
     
     
         40 . The method of  claim 39 , wherein the PG is selected from trifluoroacetyl, Cbz, and Boc.